The broad, long term objective of this project is to reduce morbidity and mortality caused by papillary thyroid carcinoma (PTC) which accounts for >80% of all thyroid cancers. PTC displays high heritability suggesting the existence of genes that when mutated predispose to PTC. So far no such inherited gene has been dentified. In preliminary experiments, linkage analysis in affected families has been used to discover several loci in the genome that likely harbor such genes. The first goal of this research is to refine the ocalization of these putative genes by linkage analysis and allelic association analysis using high-throughput technology. Once the loci have been narrowed to at most several megabases of DNA, positional cloning and mutation screening will be used to pinpoint the predisposing gene mutations. The discovery of genes predisposing to PTC would make it possible to predict who is, and who is not at high risk to develop PTC, allowing clinical screening and early detection, leading to public health benefits. Moreover, the elucidation of the genetic pathways leading to PTC allows therapeutic drugs and preventative strategies to be designed.